DESCRIPTION: Dr. Pestka's overall objective is to elucidate the mechanisms of regulation and function of the interferon gamma receptor. Interferon gamma plays a critical role in the regulation of the immune system and is active on virtually all tissues. The actions of IFN gamma are mediated by its receptor. Dr. Pestka s laboratory and other laboratories have identified two chains of the gamma receptor, gR1 and gR2, that are required for receptor activity and their cDNAs have been cloned. The current proposal focuses on the mechanism of regulation of expression of the gamma receptor, its mechanism of signal transduction, and the elucidation of possibly new biochemical pathways involved in gamma function. Seven specific aims are proposed as follows: 1. to determine the role of Jak kinases in the specificity of signal transduction; 2. to complement cells lacking Jak kinases with synthetic receptors; 3. to determine the structure and function of the gene for the interferon gR2 chain; 4. to determine the structural requirements for function of the interferon gamma R1 and R2 chains; 5. to delineate other proteins and pathways linked to the interferon gamma receptor; 6. to determine the role of the second interferon gamma receptor chain, gR2, in various responses; and 7. to identify additional accessory factors beyond AF1 (now called gamma R2) involved in the action of gamma interferon.